Efficacy of PARP Inhibitor Rucaparib in Orthotopic Glioblastoma Xenografts Is Limited by Ineffective Drug Penetration into the Central Nervous System

Parrish, Karen E.; Cen, Ling; Murray, J. C.; Calligaris, David; Kizilbash, Sani H.; Mittapalli, Rajendar K.; Carlson, Brett L.; Schroeder, Mark A.; Sludden, Julieann; Boddy, Alan V.; Agar, Nathalie Y.R.; Curtin, Nicola J.; Elmquist, William F.; Sarkaria, Jann N.

doi:10.1158/1535-7163.mct-15-0553

Cited by 79 publications

(66 citation statements)

References 51 publications

(60 reference statements)

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“…The in vivo TAL dosing strategy and CNS distribution evaluation in this study were pertinent because the plasma concentration of TAL achieved two hours after drug administration was similar to that measured in the phase I clinical trial (67.1 nmol/L in mice vs. 50 nmol/L in human)(44). Comparing the pharmacokinetics of TAL to other PARP inhibitors, the brain-to-plasma concentration ratio for TAL (0.02) is lower than that of rucaparib (0.11), which also lacked efficacy in orthotopic glioma models(42). Alternatively, veliparib has a much higher brain-to-plasma concentration ratio (0.47) than either TAL or rucaparib despite the efflux liability of veliparib to MDR1 and BCRP (16, 45).…”

Section: Discussionmentioning

confidence: 99%

Restricted Delivery of Talazoparib Across the Blood–Brain Barrier Limits the Sensitizing Effects of PARP Inhibition on Temozolomide Therapy in Glioblastoma

Kizilbash

Gupta

Chang

et al. 2017

Molecular Cancer Therapeutics

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Poly (ADP-ribose) polymerase PARP inhibitors, including talazoparib (TAL), potentiate temozolomide (TMZ) efficacy in multiple tumor types, however TAL-mediated sensitization has not been evaluated in orthotopic glioblastoma (GBM) models. This study evaluates TAL ± TMZ in clinically relevant GBM models. TAL at 1–3 nmol/L sensitized T98G, U251 and GBM12 cells to TMZ, and enhanced DNA damage signaling and G2/M arrest in vitro. In vivo cyclical therapy with TAL (0.15 mg/kg twice daily) combined with low dose TMZ (5 mg/kg daily) was well tolerated. This TAL/TMZ regimen prolonged tumor stasis more than TMZ alone in heterotopic GBM12 xenografts [median time to endpoint: 76 days vs. 50 days TMZ (p=0.005), 11 days placebo (p <0.001)]. However, TAL/TMZ did not accentuate survival beyond that of TMZ alone in corresponding orthotopic xenografts (median survival 37 vs. 30 days with TMZ (p=0.93), 14 days with placebo, p<0.001). Average brain and plasma TAL concentrations at 2 hours after a single dose (0.15 mg/kg) were 0.49±0.07 ng/g and 25.5±4.1 ng/ml, respectively. The brain/plasma distribution of TAL in Bcrp−/− versus WT mice did not differ, while the brain/plasma ratio in Mdr1a/b−/− mice was higher than WT mice (0.23 vs. 0.02, p<0.001). Consistent with the in vivo brain distribution, overexpression of MDR1 decreased TAL accumulation in MDCKII cells. These results indicate that TAL has significant MDR1 efflux liability that may restrict delivery across the blood-brain barrier, and this may explain the loss of TAL-mediated TMZ sensitization in orthotopic versus heterotopic GBM xenografts.

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Section: Discussionmentioning

confidence: 99%

Restricted Delivery of Talazoparib Across the Blood–Brain Barrier Limits the Sensitizing Effects of PARP Inhibition on Temozolomide Therapy in Glioblastoma

Kizilbash

Gupta

Chang

et al. 2017

Molecular Cancer Therapeutics

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“…25 These studies apparently explained that the expression level of INPP4B was negatively correlated F I G U R E 5 Effect of rucaparib on cell proliferation and apoptosis in both SaOS2 and U2OS cells. 29,30 However, the effect of rucaparib on the treatment of OS has not been investigated. A, B, MTT assay results showed that rucaparib significantly reduced cell viability at a dose-dependent and time-dependent manners.…”

Section: Discussionmentioning

confidence: 99%

Retracted: Inositol polyphosphate‐4‐phosphatase type II and rucaparib treatment inhibit the growth of osteosarcoma cells dependent on phosphoinositide 3‐kinase/protein kinase B pathway

Dong

Yang

et al. 2018

J of Cellular Biochemistry

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Osteosarcoma (OS) is an aggressive malignant tumor of bone, which often occurs in children and adolescents. Currently, the effective method for the treatment of OS is still limited. The study aimed to investigate the synergistic antitumor effect of inositol polyphosphate-4-phosphatase, type-II (INPP4B) and rucaparib on OS cells. The expression levels of INPP4B in OS tissues and OS cell lines were examined by quantitative real-time polymerase chain reaction and Western blot analysis. SaOS2 and U2OS cells were then transfected with overexpression vector of INPP4B or were treated with different concentrations of rucaparib, and cell viability, cell cycle, and apoptosis were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and flow cytometry. Western blot assay uncovered the combined effects of INPP4B and rucaparib on cell cycle, apoptosis and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signal pathway. Further, the tumor formation was examined in vivo. Results showed that INPP4B was low expressed in OS tissues and in OS cell lines. INPP4B overexpression significantly decreased cell viability and induced apoptosis in SaOS2 and U2OS cells. Additionally, rucaparib remarkably reduced cell viability in a dose-dependent and time-dependent manner. Meanwhile, rucaparib suppressed cell cycle progression in the S phase and promoted apoptosis in a dose-dependent manner. Further, combination of INPP4B overexpression and rucaparib declined Myc, cyclin E1 and cyclin D1 expressions, enhanced Bad, Bax, and cleaved-caspase-3 expressions, and blocked PI3K/AKT signal pathway in SaOS2 and U2OS cells. Finally, combination of INPP4B overexpression and rucaparib inhibited tumor formation in vivo. The study demonstrated that INPP4B and rucaparib exhibited synergistic antitumor effect by regulating PI3K/AKT pathway in OS cells.

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“…For example, one study reported that rucaparib had poor penetration into the CNS, suggesting it would have limited activity as a temozolomide sensitizer in GBM (15). Recently, however, the field has been revitalized by the demonstration that olaparib penetrates GBM at therapeutic levels in situ in patients (16), and also by promising toxicity and efficacy data arising from a phase I study of veliparib in combination with whole brain radiotherapy for brain metastases (17), and several phase I studies are now underway.…”

Section: Manuscriptmentioning

confidence: 99%

GBM radiosensitizers: dead in the water…or just the beginning?

et al. 2017

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Abstract:The finding that most GBMs recur either near or within the primary site after radiotherapy has fueled great interest in the development of radiosensitizers to enhance local control. Unfortunately, decades of clinical trials testing a wide range of novel therapeutic approaches have failed to yield any clinically viable radiosensitizers (1). However, it is well-recognized that temozolomide chemotherapy is administered concurrently with radiotherapy specifically as a radiosensitizer. Furthermore, it can be argued that many of the previous radiosensitizing strategies, for GBM and many other tumor types were not backed by firm pre-clinical evidence supporting a synergistic or additive interaction (2). Another poorly understood variable is lack of blood-brain barrier penetration as potential limitation for treatment efficacy, as until recently most clinical trials did not assess the actual drug levels in GBM tumors. Finally, despite an understanding that DNA repair status was an important variable for radiotherapy treatment responses dating back to the 1970's, the actual DNA repair pathways and proteins were only fully elucidated in the last decade. Here, we present recent progress in the use of small molecule DNA damage response inhibitors as GBM radiosensitizers. In addition, we discuss the latest progress in targeting hypoxia and oxidative stress for GBM radiosensitization. Introduction. The finding that most GBMs recur either near or within the primary site after radiotherapy has fueled great interest in the development of radiosensitizers to enhance local control. Unfortunately, decades of clinical trials testing a wide range of novel therapeutic approaches have failed to yield any clinically viable radiosensitizers (1). However, it is well-recognized that temozolomide chemotherapy is administered concurrently with radiotherapy specifically as a radiosensitizer. Furthermore, it can be argued that many of the previous radiosensitizing strategies, for GBM and many other tumor types were not backed by firm pre-clinical evidence supporting a synergistic or additive interaction (2). Another poorly understood variable is lack of blood-brain barrier penetration as potential limitation for treatment efficacy, as until recently most clinical trials did not assess the actual drug levels in GBM tumors. Finally, despite an understanding that DNA repair status was an important variable for radiotherapy treatment responses dating back to the 1970's, the actual DNA repair pathways and proteins were only fully elucidated in the last decade. Here, we present recent progress in the use of small molecule DNA damage response inhibitors as GBM radiosensitizers. In addition, we discuss the latest progress in targeting hypoxia and oxidative stress for GBM radiosensitization. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation

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Efficacy of PARP Inhibitor Rucaparib in Orthotopic Glioblastoma Xenografts Is Limited by Ineffective Drug Penetration into the Central Nervous System

Cited by 79 publications

References 51 publications

Restricted Delivery of Talazoparib Across the Blood–Brain Barrier Limits the Sensitizing Effects of PARP Inhibition on Temozolomide Therapy in Glioblastoma

Restricted Delivery of Talazoparib Across the Blood–Brain Barrier Limits the Sensitizing Effects of PARP Inhibition on Temozolomide Therapy in Glioblastoma

Retracted: Inositol polyphosphate‐4‐phosphatase type II and rucaparib treatment inhibit the growth of osteosarcoma cells dependent on phosphoinositide 3‐kinase/protein kinase B pathway

GBM radiosensitizers: dead in the water…or just the beginning?

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